General Information

Synjardy is a combination of empagliflozin and metformin, two medicines with complementary mechanisms of action. Empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor, removes excess glucose through the urine by blocking glucose re-absorption in the kidney. Metformin lowers glucose production by the liver and its absorption in the intestine.

Synjardy is specifically indicated an adjunct to diet and exercise to improve glycemic control in patients >10 years of age with type 2 diabetes mellitus who are not adequately controlled on a regimen containing empagliflozin or metformin, or in patients already being treated with both empagliflozin and metformin.

Mechanism of Action

Synjardy is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin, a biguanide. Empagliflozin: Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Metformin hydrochloride: Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. It is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike SUs, metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or normal subjects (except in special circumstances) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Side Effects

Adverse effects associated with the use of Synjardy may include, but are not limited to, the following: 

Most common adverse reactions associated with empagliflozin:

• urinary tract infection
• female genital mycotic infections.

Most common adverse reactions associated with metformin:

• diarrhea
• nausea/vomiting
• flatulence
• abdominal discomfort
• indigestion
• asthenia
• headache

Synjardy comes with a Black Box Warning for the risk of lactic acidosis, a serious metabolic complication that can occur due to metformin accumulation during treatment with Synjardy. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment and acute congestive heart failure.

Dosing/Administration

Synjardy is supplied as a tablet for oral administration. Synjardy comes in the following dose strengths:

• 5 mg empagliflozin/500 mg metformin hydrochlorideth
• 5 mg empagliflozin/1000 mg metformin hydrochloride
• 12.5 mg empagliflozin/500 mg metformin hydrochloride
• 12.5 mg empagliflozin/1000 mg metformin hydrochloride

Individualize the starting dose of Synjardy based on the patient’s current regimen:

• In patients on metformin, switch to Synjardy containing empagliflozin 5 mg with a similar total daily dose of metformin.
• In patients on empagliflozin, switch to Synjardy containing metformin 500 mg with a similar total daily dose of empagliflozin.
• In patients already treated with empagliflozin and metformin, switch to Synjardy containing the same total daily doses of each component.
• Take Synjardy twice daily with meals with gradual dose escalation to reduce the gastrointestinal side effects due to metformin.
• In patients with volume depletion not previously treated with empagliflozin, correct this condition before initiating Synjardy.
• Adjust dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of metformin 2000 mg and empagliflozin 25 mg

Clinical Trial Results

There have been no clinical efficacy studies conducted with Synjardy; however, the bioequivalence of Synjardy to empagliflozin and metformin coadministered as individual tablets was demonstrated in healthy subjects. In patients with type 2 diabetes, treatment with empagliflozin and metformin produced clinically and statistically significant improvements in HbA1c compared to placebo. Reductions in HbA1c were observed across subgroups including age, gender, race, and baseline body mass index (BMI). 

 Pediatrics

A double-blind, randomized, placebo-controlled trial enrolled 157 patients aged 10 to 17 years with inadequately controlled type 2 diabetes. Participants were randomly assigned to one of three treatment arms for 26 weeks: empagliflozin, a DPP-4 inhibitor (linagliptin), or placebo. At the beginning of the trial, 51% of patients were taking metformin alone, 40% of patients were taking a combination of metformin and insulin, 3% of patients were taking insulin alone, and 6% of patients were not taking other medicines for diabetes. The trial found that, at week 26, treatment with empagliflozin was superior in reducing hemoglobin A1c, a measure of average blood sugar, compared to placebo. The 52 patients treated with empagliflozin had an average 0.2% decrease in hemoglobin A1c compared with an average 0.7% increase in hemoglobin A1c in the 53 patients taking placebo, representing a 0.8% decrease in hemoglobin A1c with empagliflozin as compared to placebo. Patients treated with empagliflozin also had reductions in fasting plasma glucose, a blood sugar measurement taken after not eating or drinking for at least eight hours, as compared to patients taking placebo.